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Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study.
Diabetes Care. 2020 Sep; 43(9):2066-2073.DC

Abstract

OBJECTIVE

The first-appearing β-cell autoantibody has been shown to influence risk of type 1 diabetes (T1D). Here, we assessed the risk of autoantibody spreading to the second-appearing autoantibody and further progression to clinical disease in The Environmental Determinants of Diabetes in the Young (TEDDY) study.

RESEARCH DESIGN AND METHODS

Eligible children with increased HLA-DR-DQ genetic risk for T1D were followed quarterly from age 3 months up to 15 years for development of a single first-appearing autoantibody (GAD antibody [GADA], insulin autoantibody [IAA], or insulinoma antigen-2 autoantibody [IA-2A]) and subsequent development of a single second-appearing autoantibody and progression to T1D. Autoantibody positivity was defined as positivity for a specific autoantibody at two consecutive visits confirmed in two laboratories. Zinc transporter 8 autoantibody (ZnT8A) was measured in children who developed another autoantibody.

RESULTS

There were 608 children who developed a single first-appearing autoantibody (IAA, n = 282, or GADA, n = 326) with a median follow-up of 12.5 years from birth. The risk of a second-appearing autoantibody was independent of GADA versus IAA as a first-appearing autoantibody (adjusted hazard ratio [HR] 1.12; 95% CI 0.88-1.42; P = 0.36). Second-appearing GADA, IAA, IA-2A, or ZnT8A conferred an increased risk of T1D compared with children who remained positive for a single autoantibody, e.g., IAA or GADA second (adjusted HR 6.44; 95% CI 3.78-10.98), IA-2A second (adjusted HR 16.33; 95% CI 9.10-29.29; P < 0.0001), or ZnT8A second (adjusted HR 5.35; 95% CI 2.61-10.95; P < 0.0001). In children who developed a distinct second autoantibody, IA-2A (adjusted HR 3.08; 95% CI 2.04-4.65; P < 0.0001) conferred a greater risk of progression to T1D as compared with GADA or IAA. Additionally, both a younger initial age at seroconversion and shorter time to the development of the second-appearing autoantibody increased the risk for T1D.

CONCLUSIONS

The hierarchical order of distinct autoantibody spreading was independent of the first-appearing autoantibody type and was age-dependent and augmented the risk of progression to T1D.

Authors+Show Affiliations

Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL kendra.vehik@epi.usf.edu.Forschergruppe Diabetes e.V., Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany. DFG Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.Department of Clinical Sciences, Lund University/CRC, Skane University Hospital, Malmö, Sweden.Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO.Diabetes and Metabolism, Translational Health Sciences, University of Bristol, Bristol, U.K.Diabetes Center of Excellence, University of Florida, Gainesville, FL.Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO.Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA.Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland. Department of Pediatrics, Turku University Hospital, Turku, Finland.Pacific Northwest Diabetes Research Institute, Seattle, WA.National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD.Forschergruppe Diabetes e.V., Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany. Institute of Diabetes Research, Helmholtz Zentrum München, and Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany.Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32641373

Citation

Vehik, Kendra, et al. "Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study." Diabetes Care, vol. 43, no. 9, 2020, pp. 2066-2073.
Vehik K, Bonifacio E, Lernmark Å, et al. Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study. Diabetes Care. 2020;43(9):2066-2073.
Vehik, K., Bonifacio, E., Lernmark, Å., Yu, L., Williams, A., Schatz, D., Rewers, M., She, J. X., Toppari, J., Hagopian, W., Akolkar, B., Ziegler, A. G., & Krischer, J. P. (2020). Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study. Diabetes Care, 43(9), 2066-2073. https://doi.org/10.2337/dc19-2547
Vehik K, et al. Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study. Diabetes Care. 2020;43(9):2066-2073. PubMed PMID: 32641373.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study. AU - Vehik,Kendra, AU - Bonifacio,Ezio, AU - Lernmark,Åke, AU - Yu,Liping, AU - Williams,Alistair, AU - Schatz,Desmond, AU - Rewers,Marian, AU - She,Jin-Xiong, AU - Toppari,Jorma, AU - Hagopian,William, AU - Akolkar,Beena, AU - Ziegler,Anette G, AU - Krischer,Jeffrey P, AU - ,, Y1 - 2020/07/08/ PY - 2019/12/19/received PY - 2020/05/13/accepted PY - 2020/7/10/pubmed PY - 2020/7/10/medline PY - 2020/7/10/entrez SP - 2066 EP - 2073 JF - Diabetes care JO - Diabetes Care VL - 43 IS - 9 N2 - OBJECTIVE: The first-appearing β-cell autoantibody has been shown to influence risk of type 1 diabetes (T1D). Here, we assessed the risk of autoantibody spreading to the second-appearing autoantibody and further progression to clinical disease in The Environmental Determinants of Diabetes in the Young (TEDDY) study. RESEARCH DESIGN AND METHODS: Eligible children with increased HLA-DR-DQ genetic risk for T1D were followed quarterly from age 3 months up to 15 years for development of a single first-appearing autoantibody (GAD antibody [GADA], insulin autoantibody [IAA], or insulinoma antigen-2 autoantibody [IA-2A]) and subsequent development of a single second-appearing autoantibody and progression to T1D. Autoantibody positivity was defined as positivity for a specific autoantibody at two consecutive visits confirmed in two laboratories. Zinc transporter 8 autoantibody (ZnT8A) was measured in children who developed another autoantibody. RESULTS: There were 608 children who developed a single first-appearing autoantibody (IAA, n = 282, or GADA, n = 326) with a median follow-up of 12.5 years from birth. The risk of a second-appearing autoantibody was independent of GADA versus IAA as a first-appearing autoantibody (adjusted hazard ratio [HR] 1.12; 95% CI 0.88-1.42; P = 0.36). Second-appearing GADA, IAA, IA-2A, or ZnT8A conferred an increased risk of T1D compared with children who remained positive for a single autoantibody, e.g., IAA or GADA second (adjusted HR 6.44; 95% CI 3.78-10.98), IA-2A second (adjusted HR 16.33; 95% CI 9.10-29.29; P < 0.0001), or ZnT8A second (adjusted HR 5.35; 95% CI 2.61-10.95; P < 0.0001). In children who developed a distinct second autoantibody, IA-2A (adjusted HR 3.08; 95% CI 2.04-4.65; P < 0.0001) conferred a greater risk of progression to T1D as compared with GADA or IAA. Additionally, both a younger initial age at seroconversion and shorter time to the development of the second-appearing autoantibody increased the risk for T1D. CONCLUSIONS: The hierarchical order of distinct autoantibody spreading was independent of the first-appearing autoantibody type and was age-dependent and augmented the risk of progression to T1D. SN - 1935-5548 UR - https://www.unboundmedicine.com/medline/citation/32641373/Hierarchical_Order_of_Distinct_Autoantibody_Spreading_and_Progression_to_Type_1_Diabetes_in_the_TEDDY_Study_ L2 - http://care.diabetesjournals.org/cgi/pmidlookup?view=long&amp;pmid=32641373 DB - PRIME DP - Unbound Medicine ER -
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